1772
J. Ohwada et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1767–1772
2. (a) Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.;
2500
2000
1500
1000
500
KPL-4 (PIK3CAH1047R
)
Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.;
Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.;
Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.;
Wiesmann, C.; Wong, S.; Zhu, B. Y. J. Med. Chem. 2010, 53, 1086; (b) Yaguchi, S.;
Fukui, Y.; Koshimizu, I.; Yoshimi, H.; Matsuno, T.; Gouda, H.; Hirono, S.;
Yamazaki, K.; Yamori, T. J. Natl. Cancer Inst. 2006, 98, 545; (c) Maira, S. M.;
Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chene,
P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy,
L.; Finan, P.; Sellers, W.; Garcia-Echeverria, C. Mol. Cancer Ther. 2008, 7(7), 1851.
Vehicle
q.d.
q.d. 2 weeks on-1 week off
q.d. 5 days on-2 days off
3. A homology model of PI3K
a
was constructed from the crystal structure of PI3K
c
comlex with staurosporine (PDB:1E8Z).
4. PI3Kc was expressed and purified as described previously Walker, E. H.; Pacold,
M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L.
Mol. Cell 2000, 6, 909. Crystals were grown in 100 mM Tris–HCl pH7.2, 200 mM
ammonium sulfate and 20% PEG 3350 with seeds. Diffraction data were
collected at beamlines NW12 at PF, KEK and BL41XU at SPring-8. Crystal
structures were solved by MR using the coordinates of PDB 1E8Y. 3D structure
complexes of 6, 7 and CH5132799 (1) with PI3Kc were refined to R/Rfree values
of 0.241/0.315 at 2.9 Å resolution, 0.250/0.316 at 2.5 Å, and 0.236/0.290 at
2.5 Å, respectively..
5. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Kawaguchi, K.; Koizumi, T.; Yamano,
M.; Matsuda, K.; Okada, M.; Ohta, M.; WO Patent, 1083456, 2001.
6. Nuss, J M.; Pecchi, S.; Renhowe, P A.; WO Patent, 4048365, 2004.
7. PDB ID code: 3APF
0
25
32
39
46
53
60
67
Days after tumor implantation
8. FlexX with the single interaction scan algorithm. (a) Matthias, R.; Bernd, K.;
Thomas, L.; Gerhard, K. J. Mol. Biol. 1996, 261, 470; (b) Matthias, R.; Stephan,
W.; Thomas, L. J. Comput. Aided Mater. Des. 1996, 10, 41. Virtually synthesized
compounds from 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-
pyrrolo[2,3-d]pyrimidine and available boronic acids having hydrogen bond
donor/acceptor were scored by FlexSIS docking simulations and compounds
with high FlexSIS scores were actually synthesized by Suzuki coupling. For
example, the score of 2-aminopyrimidine-5-yl was ꢁ25.5 kJ/mol, and this was
more highly prioritized than indoline-5-yl (ꢁ21.5 kJ/mol). We are publishing
these details in the near future. Filed patent: WO Patent, 018426, 2008 (Filing
date: Aug, 8, 2006).
Figure 9. In vivo efficacy of CH5132799 (1) in KPL-4 xenograft model CH5132799
was orally administered at 12.5 mg/kg for 6 weeks in three dosing schedules. Ç:
vehicle; }: q.d; 4: q.d., 2 weeks on/1 week off; h: qd, 5 days on/2 days off.
Acknowledgments
The HER2-positive human inflammatory breast cancer cell line
KPL-4 was kindly provided by Dr. J. Kurebayashi (Kawasaki Medi-
cal School, Kurashiki, Japan). We thank Drs. S. Courtney and W.
Trigg (Evotec) for synthetic assistance. We also thank the staffs
of synchrotron beamlines NW12 at PF, KEK and BL41XU at
SPring-8 for their help in data collection.
9. PDB ID code: 3APD
10. PDB ID code: 3APC
11. Quesada, M. L.; Schlessinger, R. H. J. Org. Chem. 1978, 43, 346.
12. Tanaka, H.; Yoshida, M.; Tanimura, H.; Fujii, T.; Sakata, K.; Tachibana, Y.;
Ohwada, J.; Ebiike, H.; Kuramoto, S.; Morita, K.; Yoshimura, Y.; Yamazaki, T.;
Ishii, N.; Kondoh, O.; Aoki, Y. The selective class I PI3K inhibitor CH5132799
targets human cancers harboring oncogenic PIK3CA mutations; Clin. Cancer
Res., in press.
References and notes
13. Kurebayashi, J.; Otsuki, T.; Tang, C. K.; Kurosumi, M.; Yamamoto, S.; Tanaka, K.;
Mochizuki, M.; Nakamura, H.; Sonoo, H. Br. J. Cancer 1999, 79, 707.
1. (a) Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Nat. Rev. Drug Disc. 2009, 8, 627;
(b) Bader, A. G.; Kang, S.; Zhao, L.; Vogt, P. K. Nat. Rev. Cancer 2005, 5, 921.